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Wilms Tumor: Diagnosis and Treatment of Nephroblastoma

Definition of Wilms Tumor

Wilms tumor (or nephroblastoma) is a rare malignant renal tumor in children. The tumor arises from remnants of immature tissue from renal development (Graf et al., 2003) (Metzger et al., 2005) (Kalapurakal et al., 2004) (Wu et al., 2005). The tumor was described in 1899 by German surgeon Max Wilms (1867–1918).

Epidemiology

Incidence 1/100.000 in children under 15 years, median age at diagnosis is 3.5 years. Balanced sex ratio.

Association of Wilms tumor with rare genetic syndromes:

10% of Wilms tumors are associated with congenital anomalies and genetic syndromes:

Denys-Drash syndrome:

45,X/46,XY mixed gonadal dysgenesis with variable phenotyp, renal mesangial sclerosis, Wilms' tumor (50% risk) and WT1 mutations (see below).

WAGR syndrome:

WILMS tumor in 50%, Aniridia, Genital anomalies, mental Retardation, WT1 mutations (see below).

Beckwith-Wiedemann syndrome:

4–10% risk for Wilms tumor, excessive growth at the cellular level, organ level (macroglossia, nephromegaly, hepatomegaly) or body segment level (hemihypertrophy), WT2 mutations (see below).

Perlman syndrome:

Uncommon genetic syndrome characterized by polyhydramnios, macrosomia, bilateral renal tumors with a high risk for Wilms tumor.

Fanconi anemia D1:

Generally increased tumor risk, 20% risk of Wilms tumor.

Horseshoe kidney:

2–7-fold increased risk of Wilms tumor.

Causes (Etiology) of Nephroblastoma

Tumor suppressor genes:

Wilms tumor is a classic example of loss of function mutations of tumor suppressor genes. Due to the diploid chromosome status, at least two genetic events are necessary for the complete loss of function of a tumor suppressor. In genetic syndromes or familiar Wilms tumors, the first mutation is inherited from the parents; the second mutation occurs spontaneously or during further development.

Wilms tumor suppressor gene 1 (WT1):

WT1 is located on chromosome 11p13. The gene product regulates the expression of other genes during normal kidney development.

Wilms tumor suppressor gene 2 (WT2):

WT2 is located on chromosome 11p15. The gene product is not known.

Further molecular changes:

p53 mutations, WTX mutations, LOH at 1p and 16q.

Wilms Tumor Pathology

Classical Wilms tumor:

The classical Wilm tumor (also called favorable-histology Wilms tumor) is a triphasic tumor consisting of islands of metanephritic blastema with variable epithelial and stromal components.

Anaplastic Wilms tumor:

Prominent nuclear enlargement with hyperchromasia and abnormal mitotic figures are the hallmarks of anaplastic Wilms tumor. Approximately 10% of Wilms tumors are anaplastic, they exhibit a poor prognosis even in tumor stages confined to the kidney due to their resistance to chemotherapy.

Wilms tumor with nephrogenic rests:

30% of kidneys with Wilms tumor contain embryonic cells (nephrogenic rests) within the normal renal tissue. Nephrogenic rests are differentiated according to their localization: perilobar nephrogenic rests (PLNR) or intralobar nephrogenic rests (ILNR). The presence of PLNR or ILNR leads to an increased risk of bilateral disease or developing contralateral disease in the future. Regular surveillance is recommended.

Metastases:

10% of children with Wilms tumor present with distant metastases at diagnosis, most commonly in the lungs, liver, bone and brain.

Tumor Staging

Staging classification is done after neoadjuvant chemotherapy and radical nephrectomy.

Stage I:

The tumor is limited to the kidney. The tumor does not infiltrate the ureteral or renal pelvis wall. The vessels of the renal sinus are not involved. Complete resection.

Stage II:

The tumor extends beyond the kidney (perirenal fat, renal sinus, lymph nodes), but complete resection.

Stage III:

Incomplete tumor resection, but no distant metastases.

Stage IV:

Hematogenous or distant metastases (lung, liver, bone, brain, etc.)

Stage V:

Bilateral renal involvement at initial diagnosis

Signs and Symptoms

Abdominal tumor, abdominal pain, and hematuria are typical findings. Hypertension may be caused by renin secretion in 25%. Vomiting, fever or varicoceles are rarely present. It is important to search for associated malformations such as aniridia, hemihypertrophy and genital anomalies.

Diagnostic Workup

Laboratory investigations:

Tumor markers are not available. If neuroblastoma is possible, initiate 24-hour urine collection and test for catecholamines and metanephrines.

Ultrasound imaging:

Imaging reveals a mass of the kidney. A tumor thrombus may be seen in the renal vein or vena cava.

CT or MRI of the abdomen:

The radiological differentiation between the possible childhood tumors is not always possible (differential diagnosis: neuroblastoma or lymphoma). Imaging is important to detect bilateral disease and to evaluate renal function.

Chest CT:

Staging procedure.

MIBG-Scintigraphy:

If neuroblastoma is possible.

Tumor Biopsy:

Only if the diagnosis is unclear (atypical imaging) before planned neoadjuvant chemotherapy.

Genetic testing:

If above-mentioned clinical syndromes are suspected.

Treatment of Wilms Tumor

Due to the small number of cases, treatment should be done according to the recommendations of multinational study groups. There are two different therapeutic approaches:

NWTS / COG Recommendations:

Primary surgical resection of the tumor is the initial treatment of most children according to the National Wilms Tumor Study Group (NWTS) and Children Oncology Group (COG) in the United States. The postoperative histology and tumor stage decide on adjuvant chemotherapy and radiotherapy. Neoadjuvant chemotherapy is recommended for bilateral Wilms tumors if a complete tumor resection is considered not possible (intraoperative decision) or with involvement of the inferior vena cava above the hepatic veins.

SIOP Recommendations:

Neoadjuvant chemotherapy before surgical treatment is recommended for most children, according to the Société internationale d'oncologie pédiatrique (SIOP). A primary tumor biopsy is not recommended if imaging is straightforward in children over six months and younger than 16. Neoadjuvant therapy leads to a lower tumor stage and reduces the rate of incomplete resection or tumor rupture. After nephrectomy, the postoperative tumor stage and histology decide on adjuvant chemotherapy and radiotherapy. Primary surgery is recommended for children under six months or over 16 years since malignant tumors other than Wilms tumor are more likely.

Radical Nephrectomy:

Radical nephrectomy is done via a transperitoneal approach. Key points of the operative technique are complete resection and accurate intraoperative staging of lymph nodes, liver, peritoneum, and vena cava.

Chemotherapy:

Chemotherapy is always administered as a combination chemotherapy. The most effective drugs are actinomycin-D and vincristine. If high-risk tumor stages are present, anthracyclines (epirubicin, doxorubicin) are added.

Radiotherapy:

The indication is based on the histology and the local stage after nephrectomy. Indications for radiotherapy are tumor stage III, tumor stage II with high-risk histology, and lung metastases lacking complete response after chemotherapy.

Screening:

Sonographic screening tests every 3 to 4 months should be performed in children with more than 5% risk of Wilms tumor (e.g., children with WAGR syndrome, Beckwith-Wiedemann syndrome or familial Wilms tumor).

Prognosis

90% of all children with Wilms tumor can be cured. The prognosis depends on the tumor stage and histology. Unfavorable prognostic factors are metastases present at diagnosis and tumors with high malignancy (e.g., anaplastic or blastema-dominant Wilms tumor).

References

Graf, N. & Reinhard, H. [Wilms tumors. Diagnosis and therapy].
Urologe A 2003, 42, W391-407; quiz W408-9

Kalapurakal u.a. 2004 KALAPURAKAL, J. A. ; DOME, J. S. ; PERLMAN, E. J. ; MALOGOLOWKIN, M. ; HAASE, G. M. ; GRUNDY, P. ; COPPES, M. J.: Management of Wilms’ tumor: current practice and future goals.
In: Lancet Oncol
5 (2004), Nr. 1, S. 37–46

Metzger, M. L. & Dome, J. S. Current therapy for Wilms' tumor.
Oncologist, 2005, 10, 815-826.

Wu u.a. 2005 WU, H. Y. ; SNYDER, 3rd ; D'ANGIO, G. J.: Wilms’ tumor management.
In: Curr Opin Urol
15 (2005), Nr. 4, S. 273–6

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